DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ANTI-INFECTIVE DRUGS ADVISORY
COMMITTEE (AIDAC) MEETING
Discussion of Issues Related to Clinical
Trial Design and Analysis in Studying Bacteremia
Due to Staphylococcus aureus and
Catheter Related Bacteremia
Thursday, October 14, 2004
8:20 a.m.
Hilton Gaithersburg
The Ballroom
620 Perry Parkway
Gaithersburg, Maryland
PARTICIPANTS
James E. Leggett, Jr., M.D., Chair
Shalini Jain, PA-C, MBA, Executive Secretary
MEMBERS
Alan S. Cross, M.D.
Celia J. Maxwell, M.D.
Jan E. Patterson, M.D.
Joan F. Hilton, Sc.D., MPH
John S. Bradley, M.D.
Donald M. Poretz, M.D.
Samuel D. Maldonado, M.D.,
MPH
(Industry Representative)
John E. Edwards, Jr., M.D.
CONSULTANTS, SPECIAL GOVERNMENT EMPLOYEES (VOTING)
Thomas R. Fleming, Ph.D.
Christopher A. Ohl, M.D.
L. Barth Reller, M.D.
Nathan M. Theilman, M.D., MPH
CONSULTANT, FEDERAL EMPLOYEE (VOTING)
Patrick R. Murray, Ph.D.
FDA
Mark Goldberger, M.D.
Sumathi Nambiar, M.D.
John H. Powers, M.D.
Alfred Sorbello, D.O.
Janice Soreth, M.D.
C O N T E N T S
Call to Order and Opening Remarks:
James E. Leggett, Jr., M.D. 5
Conflict of Interest Statement:
Shalini Jain, PA-C, MBA 8
Opening Comments:
Janice Soreth, M.D. 11
Regulatory History of Bacteremia Indications:
Alfred Sorbello, D.O. 23
Questions from Committee 40
Epidemiology of S. aureus Bacteremia:
Sumathi Nambiar, M.D. 55
Questions from Committee 74
Microbiological Considerations in Diagnosing
S. aureus Bacteremia:
Patrick Murray, Ph.D. 82
Questions from Committee 103
Open Public Hearing--Extra Session 109
Francis P. Tally, M.D.,
Cubist Pharmaceuticals Inc.
Clinical Trials Issues with Studies of S. aureus
Bacteremia:
John H. Powers, M.D. 131
Questions from Committee 173
Open Public Hearing 208
Tim Henkel, M.D., Ph.D.,
Vicuron
Pharmaceuticals 209
Charles Knirsch, M.D., MPH,
Pfizer
Pharmaceuticals 222
C
O N T E N T S (Continued)
David Shlaes M.D., Ph.D., Idenix
Issues in Studying Catheter-Related Bacteremia:
Janice Pohlman, M.D. 247
Questions from Committee 269
Questions to Committee and Discussion 272
Summary 366
P R O C E E D
I N G S
Call to Order and Opening Remarks
DR.
LEGGETT: Good morning. Today we are gathered to discuss issues
related to clinical-trial design and analysis in studying bacteremia due to
Staphylococcus aureus as well as issues related to clinical-trial design or
analysis in studying catheter-related bacteremia.
It
is going to be, I hope, not a terribly eventful day but eventful,
nonetheless. I think that the problem
that we are faced with, as clinicians, I faced on Friday when I was asked to
see two patients, one a recently end-stage renal-disease patient with diabetes
who has had three MRSA hemodialysis catheter infections since July when she
started dialysis requiring the removal of the catheter and, at the same time,
was called to see a patient because they had Gram-positive cocci in clusters
from their one of two blood cultures and it turned out to be coagulate-negative
Staph and who cared.
So
I think that is going to be sort of the crux of a lot of the problems today.
To
get started, why don't we go around the table and have everyone introduce
themselves.
DR.
MAXWELL: I'm Celia Maxwell, the
Assistant Vice President for Health Sciences at Howard University, an adult
infectious diseases specialist.
DR.
BRADLEY: I am John Bradley, Pediatric
Infectious Diseases, from Children's Hospital in San Diego.
DR.
OHL: Chris Ohl, Section on Infectious
Diseases, Wake Forest University School of Medicine.
DR.
HILTON: Joan Hilton. I am on the Biostatistics Faculty at
University of California, San Francisco.
DR.
MURRAY: Pat Murray, Director of Microbiology
at the NIH Clinical Center.
DR.
RELLER: Barth Reller, Division of
Infectious Diseases and International Health and Director of Clinical
Microbiology, Duke University Medical Center.
DR.
LEGGETT: Jim Leggett, Infectious
Diseases, Providence Portland Medical Center and the Oregon Health and Sciences University.
DR.
CROSS: Alan Cross, Center for Vaccine
Development, University of Maryland.
DR.
FLEMING: Thomas Fleming, Department of
Biostatistics, University of Washington.
DR.
MALDONADO: Sam Maldonado, Global and
Regulatory Affairs, Johnson & Johnson.
I am the industry representative to this committee.
DR.
PATTERSON: Jan Patterson, Medicine
Infectious Diseases, University of Texas Health Science Center, San Antonio and
South Texas Veterans Healthcare System.
DR.
THEILMAN: Nathan Theilman, Division of
Infectious Diseases and International Health, Duke University Medical Center.
DR.
PORETZ: Donald Poretz, Infectious
Diseases in Fairfax, Virginia.
DR.
NAMBIAR: Sumathi Nambiar, Division of
Anti-Infective Drug Products, FDA.
DR.
SORBELLO: Fred Sorbello, Medical
Officer, FDA.
DR.
POWERS: John Powers, Lead Medical
Officer for Antimicrobial Drug Development and Resistance Initiatives in ODE IV
at FDA.
DR.
SORETH: Good morning. I am Janice Soreth, the Division Director for
Anti-Infectives. Let me take the
opportunity to introduce in absentia our Office Director, Dr. Mark Goldberger,
who is on his way. But another person
who is actually here and who directs a sister division, that of Special
Pathogens and Immunologic Drugs which also regulates antibiotic
development. That would be Dr. Renata
Albrecht who sits behind me here.
MS.
JAIN: I am Shalini Jain, Executive
Secretary for the Anti-Infective Drugs Advisory Committee.
Conflict of Interest Statement
MS.
JAIN: Before we begin the meeting, I
need to read a conflict-of-interest statement.
The following announcement addresses the issue of conflict of interest
issues associated with this meeting and is made a part of the record to preclude
even the appearance of such.
Based
on the agenda, it has been determined that the topics of today's meeting are
issues of broad applicability and there are no products being approved. Unlike issues before a committee in which a
particular product is discussed, issues of broader applicability involve many
industrial sponsors in academic institutions.
All
Special Government Employees have been screened for their financial interests
as they may apply to the general topics at hand. To determine if any conflict of interest
existed, the agency has reviewed the agenda and all relevant financial
interests as reported by the meeting participants.
The
Food and Drug Administration has granted general-matters waivers to the Special
Government Employees participating in this meeting who require a waiver until
Title 18 United States Code Section 208.
A copy of waiver statements may be obtained by submitted a written
request to the agency's Freedom of Information Office, Room 12A-30 of the
Parklawn Building.
Because
general topics impact so many entities, it is not practical to recite all
potential conflicts of interest as they may apply to each member, consultant
and guest speaker. FDA acknowledges that
there may be potential conflicts of interest but, because of the general nature
of the discussions before the committee, these potential conflicts are
mitigated.
With
respect to FDA's invited industry representative, we would like to disclose
that Dr. Samuel Maldonado is participating in this meeting as a non-voting
industry representative acting on behalf of regulated industry. Dr. Maldonado's role on this committee is to
represent industry interests in general and not any one particular company. Dr. Maldonado is employed by Johnson &
Johnson.
In
the event that the discussions involve any other products or firms not already
on the agenda for which FDA participants has a financial interest, the
participants' involvement and their exclusion will be noted for the record.
With
respect to all other participants, we ask, in the interest of fairness, that
all persons making statements or presentations disclose any current or previous
financial involvement with any firm whose products they may wish to comment
upon.
Thank
you.
DR.
LEGGETT: Janice, would you like to start?
Opening Comments
DR.
SORETH: Good morning, Dr. Leggett and
special thanks for the academic quarter this morning, members of the advisory
committee, FDA and industry colleagues and other members of the audience.
(Slide.)
I
would like to begin today's talks by telling you what we are going to talk
about today followed by actually talking about it, then summarizing what we
already told you as a segue to the discussion.
I promise we will finish before midnight.
This
is the story of blood and guidance going a bit bad, that of bacteremia as an
indication.
(Slide.)
I
am going to take us first through the District of Columbia, Rockville and White
Oak--you will understand what I mean in just a moment--followed by a tour, very
briefly, of Hollywood, the Washington Redskins, the NHL lockout, Monday morning
quarterbacking--that would be the discussion period--and wrapping up with
credits. I promise you I have not yet
lost my mind.
(Slide.)
We
are back in the District of Columbia. It
is pre-1965. I am in second grade. We have been talking about bacteremia,
sepsis, bacteremic sepsis, septicemia, primary bacteremia and secondary
bacteremia for a long, long time, ever since the FDA was solely located in the
District.
As
far as the Org chart goes back then, and this is all oral history, we were the
Bureau of Biological and Physical Sciences, the Division of Pharmacology and we
were a branch, I think, of Antibiotics.
As I said, my knowledge of this era is entirely derivative.
(Slide.)
Let's
fast-forward to Rockville of the '70s and the '80s where the language for
bacteremia and septicemia began to make it into package inserts. We will hear more about this historical
framework and its details through to the 1990s and the present from Dr. Fred
Sorbello this morning.
The
Org chart was changing. We were becoming
the Bureau of Biological and Physical Sciences, Division of Pharmacology to the
Bureau of Drugs and Biologics, Division of Anti-Infective and, finally, the
Center for Drug Evaluation and Research.
I realize only now I forgot to put Crystal City on there because, once
we went from the District, we went to Crystal City which is in Virginia and
then, ultimately, to Rockville and Gaithersburg, which is where we are now.
The
Division was morphing at the same time.
It was growing. Back in the '70s
and '80s, we were the Division of Anti-Infectives. We were one entity that took care of regulation
of antibiotics, anti-infectives, anti-parasitics, topical antiseptics,
dermatologics, ophthalmologics, anti-fungals, T.B. drugs and antivirals. I am sure I left something out. Let me know at the break.
There
was a split, then, that happened in the latter '80s. I think it was about '88 when the development
of HIV therapies took off, as it should.
So we split and became the Division of Antiviral Drugs as well as the
Division of Anti-Infectives. The
Antiviral therapies together with the Antifungals and the TB drugs, then, went
to the Division of Antivirals.
This
is the late '80's, early '90's.
(Slide.)
By
the time we hit mid-'90's, maybe about 1996, we, as two divisions, were large
again. Portfolios were growing. So we decided to morph at that point into a
third division. So the Ur-Division, as I
like to call it, of Anti-Infectives then became Anti-Infectives, Antivirals and
Special Pathogens and Immunologic Drug Products directed by Dr. Renata
Albrecht.
The
portfolio from Anti-Infectives of quinolones split off to Special
Pathogens. I believe chronic fatigue and
AIDS wasting type of drugs and transplant products and antifungals and
antiparasitics also went to Special Pathogens.
So
we are now three divisions under the leadership of Dr. Mark Goldberger. It is pertinent--the background is pertinent
to today because the topics really touch all of us within the office and
particularly Anti-Infectives and Special Pathogens. We need to be careful as we write the music
that we sing from the same sheet of music.
I
think more on the history of what we have struggled with as a word, bacteremia,
septicemia, will be discussed later today not only by Dr. Fred Sorbello but
also, in terms of clinical-trial design considerations by Dr. John Powers, by
Dr. Janice Pohlman as well as Dr. Sumathi Nambiar.
(Slide.)
As
to the future, we are moving in 2005, we are told, to White Oak. Shalini, correct me if I am wrong, but I
think all that AC meetings will take place there.
MS.
JAIN: Actually no. They won't be able to actually accommodate
the size.
DR.
SORETH: Wonderful. Okay.
To be determined later. Shalini
was just saying that we won't necessarily have the AC meetings at White
Oak. It is our combined campus, a dream
that we have maintained at FDA for a long, long time. Some would say a nightmare, but
whatever. It is off New Hampshire
around the Beltway for Washingtonians.
This
is the laboratory building. Our building
is off to that side. I am a little
challenged directionally. I would submit
to you that we sincerely hope to have the guidance in this arena tucked away by
the time we move to White Oak. So, see,
we have a challenge.
(Slide.)
Hollywood,
where we are told nothing is impossible, where every scientist should remove
the word "impossible" from his lexicon. Christopher Reeve. Nothing is impossible.
(Slide.)
Except
maybe when it comes to the breakdown of skin, invasion of the blood stream and
infection of the patient followed by cardiac arrest, heart failure, coma and
death, for Superman was no match for a bloodstream infection.
(Slide.)
I
think our meeting today will highlight that it takes extraordinary individuals
to recognize that investment and effort in the discovery of new antibiotics and
in the treatments for serious infections, like Staphylococcus aureus
bacteremia, are indeed worth it in the long run. And I know that some of these extraordinary
individuals are in this room today.
They
are prescribing physicians. They are
academicians. They are industry
colleagues. They are FDA colleagues. They are support staff all of whom have, at
heart, the same mission.
(Slide.)
So
what do the Skins have to do with this?
Well, you have to ask yourself the question what do Joe Gibbs, who is
the Head Coach of the Washington Redskins, and the FDA have in common? I will preface my comments by saying I am a
die-hard Eagles fan but it is not why I say this.
Just
like Joe Gibbs, we thought we had put all the right pieces together on the team
with the catheter-related blood-stream infection guidance. That is 1999 and Dr. Janice Pohlman will tell
us a lot more about that later today.
And, just like Joe Gibbs, we watched as the monster just wouldn't get
up.
(Slide.)
We
discussed the catheter-related blood-stream infection guidance hereafter known
as CRBSI at a 1999 advisory committee meeting.
Most of you were probably not here then because we had a different
committee there. But I know Dr. Barth
Reller was there. The U.S. stats would
tell us that roughly there are 200,000 or 400,000 episodes per year. We should be able to study it.
Mortality
attributable somewhere between 10, 25 percent; we thought a definable case
definition--we thought. Lo and behold,
sponsors, many of them, now tell us there are numerous reasons why they have
hit the boards. But I would ask, don't
blame it on my heart; blame it on my youth.
(Slide.)
The
NHL lockout is pertinent here because success, beyond being tied to this year's
salary cap, is determined not by knowing where the puck is, rather knowing
where the puck is going to be, which is sometimes, maybe often, unpredictable
which is probably why they don't want a salary cap in the first place. But the increasing incidence of Staph aureus
bacteremia paralleled by a rise in infective endocarditis, I think, foreshadows
where major players need to position themselves to win, to develop effective
therapies whose risk/benefit ratio we think we understand so that, ultimately,
patients and their prescribing physicians can benefit from this.
(Slide.)
The
issues for discussion are many. Dr. John
Powers will cover these in great detail.
I have made some excerpts and highlights from his talk that will come
later today. But I want you to bear them
in mind as you go through today's discussions and talks. Should primary bacteremia due to Staph
aureus, PBSA, be an indication? And what
exactly would a healthy development program look like? What patient populations would be included in
such a program?
And,
just as importantly, would there be populations that should be excluded,
because we are not really sure they have an infection? Do they have a lab finding? Should endocarditis due to Staph aureus be a
separate indication?
(Slide.)
More
issues for discussion. Should we grant a
separate catheter-related blood-stream infection indication in its own
right? Does it have merit? Does it lack merit? Or, do we fold it into a more general
clinical-trial experience and product label under the rubric of primary
bacteremia due to Staph aureus or under the rubric of complicated skin
infections?
If
we go the separate way, what additional information would you suggest be
collected before, or while, treating other serious Staph aureus infections?
(Slide.)
Finally,
what role do preclinical and early clinical studies play in setting the stage
for faster, larger clinical trials? We
are cognizant of the fact that, in many ways, in drug development, as in life,
time and money are our enemies. We sweat
the small stuff and we ask you today to do the same.
How
many positive blood cultures are required prior to entry into a primary
bacteremia due to Staph aureus clinical trial?
(Slide.)
Last,
screening patients for admission into these clinical trials appears to be
complicated. Do you have any thoughts or
advice for us as to a general approach?
(Slide.)
I
would like to thank Shalini Jain, our Exec Sec contact and organizer for
today's meeting who answered numerous phone calls, E-mails and cell-phone calls
way later than anyone should have made them, myself included; our Office
Director, Mark Goldberger; John Powers; Ed Cox: and Leo Chan; and, at the
Division level, my ever supportive reliable deputy, Lilian Gravrilovich and
members of the division, Sumathi Nambiar, Janice Pohlman and Fred Sorbello.
I
will stop there and turn the podium back over to Dr. Leggett.
DR.
LEGGETT: Thank you.
Let's
move on to the Regulatory History of Bacteremia Indications which will be done
by Dr. Sorbello.
Regulatory History of Bacteremia
Indications
DR.
SORBELLO: Good morning. I am Fred Sorbello, Medical Officer at the
Division of Anti-Infective Drug Products at FDA.
(Slide.)
My
presentation today will focus on the regulatory history of bacteremia and some
of the early regulatory history of catheter-related blood-stream infections as
labeled blood-stream infection indications.
(Slide.)
I
wanted to start with an historical time line to help to focus a little bit on
the history of the development of this whole issue from a regulatory
perspective. It really began prior to
1992, 1993. As Dr. Soreth had described,
there were various types of terminology that were being used in the setting of
labeling for blood-stream infections.
In
1992, the FDA developed a document called Points to Consider. This was a very important document because it
was designed to assist investigators on how to formulate drug-development plans
for infective agents. Since that time, there
have been several anti-infective drug advisory committee meeting where the
issue has been discussed, including 1993, 1998 and 1999 and, obviously, at the
meeting today.
(Slide.)
Just
to give you a little bit of a perspective on the terminology that has been used
for blood-stream infections in antimicrobial, I just have a chart to kind of
compare the historical terminology versus what is used currently. Historically, labels would include terms such
as bacteremia or septicemia or bacteremia/septicemia, bacterial septicemia or
septicemia (including bacteremia.)
Today,
what is used currently is terminology that is in accordance with the Points to
Consider document which is basically site-specific indications with bacteremia
included if bacteremic patients were involved and assessed adequately within
the particular trials.
To give you a little more perspective on the labeling indications prior to 1992, 1993, the terms "bacteremia" and "septicemia" were those that were used most commonly.